Dendritic cells (DCs) in the epithelia and underlying lymphoid tissues (plasmacytoid and myeloid DCs, PDCs and MDCs) of the oral/nasal cavity coordinate innate and adaptive responses directing the efficiency of mucosal vaccines. DCs produce and respond to innate factors (type I IFNs) to contribute instantly and activated DCs (expressing high IL-12, IL-15, costimulatory molecules) present antigens to initiate strong adaptive T and B cell responses, culminating in protective immunity. Vaccine efficacy is maximized when TNF and TLR family members are signaled to activate DCs. We are pursuing CpG-C immunostimulatory oligodeoxynucleotides (ISS-ODNs) to efficiently activate both PDCs and B cells in the tonsillar tissue to augment immunity against HIV. We postulate that CpG-C ISS-ODN will serve multiple purposes to induce PDCs to secrete type I IFNs and favor DC and B cell activation as well as directly activate B cells. This stimulated milieu will drive innate and Th1 type adaptive responses to prevent new or control established infections systemically and at distal mucosae. Collectively we are utilizing chemically inactivated virus, AT-2 virus, as a vaccine candidate that provides a wealth of antigenic determinants to elicit broad-acting immunity upon presentation by activated DCs. Distinctively, we will compare wild type AT-2 virus to a mutated form in which the V1V2 regions of envelope have been deleted, (V1V2, rendering the virus more sensitive to Ab neutralization. We theorize that the resulting open envelope conformation exposes the neutralization-sensitive epitope and that AT-2 deltaV1V2 might induce particularly effective neutralizing Abs in addition to broad T cell responses. Employing the SIV-macaque system, we will determine whether (i) CpG-C ISS-ODN activation of tonsillar DCs/B cells augments immunity against orally applied AT-2 SIV and (ii) AT-2 deltaV1V2 induces more potent neutralizing Ab responses compared to native AT-2 SIV while still inducing solid T cell immunity. We will determine how effective this strategy is in priming naive animals to protect them against infectious mucosal challenge as well as whether this regimen can be applied as an immune therapy to infected animals to control virus once anti-retroviral therapy has ceased. This work will reveal pertinent details about combined CpG-C ISS-ODN/AT-2 virus strategies to enrich oral/nasopharyngeal vaccination to protect against HIV and other infections transmitted across mucosal surfaces while fortifying existing immunity to eradicate infection.